Abstract

Remarkable progress has been made in the field of anti-tumor immunity, nevertheless many questions are still open. Thus, even though memory T cells have been implicated in long-term anti-tumor protection, particularly in prevention of cancer recurrence, the bases of their variable effectiveness in tumor patients are poorly understood. Two types of memory T cells have been described according to their traffic pathways: recirculating and tissue-resident memory T cells. Recirculating tumor-specific memory T cells are found in the cell infiltrate of solid tumors, in the lymph and in the peripheral blood, and they constantly migrate in and out of lymph nodes, spleen, and bone marrow. Tissue-resident tumor-specific memory T cells (TRM) permanently reside in the tumor, providing local protection.Anti-PD-1/PD-L1, a type of immune checkpoint blockade (ICB) therapy, can considerably re-invigorate T cell response and lead to successful tumor control, even in patients at advanced stages. Indeed, ICB has led to unprecedented successes against many types of cancers, starting a ground-breaking revolution in tumor therapy. Unfortunately, not all patients are responsive to such treatment, thus further improvements are urgently needed. The mechanisms underlying resistance to ICB are still largely unknown. A better knowledge of the dynamics of the immune response driven by the two types of memory T cells before and after anti-PD-1/PD-L1 would provide important insights on the variability of the outcomes. This would be instrumental to design new treatments to overcome resistance.Here we provide an overview of T cell contribution to immunity against solid tumors, focusing on memory T cells. We summarize recent evidence on the involvement of recirculating memory T cells and TRM in anti-PD-1/PD-L1-elicited antitumor immunity, outline the open questions in the field, and propose that a synergic action of the two types of memory T cells is required to achieve a full response. We argue that a T-centric vision focused on the specific roles and the possible interplay between TRM and recirculating memory T cells will lead to a better understanding of anti-PD-1/PD-L1 mechanism of action, and provide new tools for improving ICB therapeutic strategy.

Highlights

  • T cells are major players of anti-tumoral immunity

  • As concerns T-cell infiltrated tumors, it is conceivable that tumor antigen-specific TRM, that permanently reside in the tumor bed and are chronically antigen-exposed, display more evident signs of exhaustion than recirculating memory T cells, which are intermittently exposed to tumor-derived antigens, e.g. in tumor-draining lymph nodes (LNs), as suggested by studies on TRM-like cells in human urinary bladder cancer [113]

  • We would like to stress that, among other mechanisms, failure of T cell response in the majority of anti-PD-1/PD-L1-treated cancer patients might derive from insufficient re-invigoration of either TRM or recirculating memory T cells, and from a non-productive interplay between the two types of T cells (Figure 3)

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Summary

Introduction

T cells are major players of anti-tumoral immunity. During the induction phase of an adaptive immune response against cancer cells, dendritic cells (DCs) uptake tumor antigens released by damaged/dying tumor cells and migrate to secondary lymphoid organs, such as tumor-draining lymph nodes (LNs). The effectiveness of ICB, even though only in some of the patients, supports the concept that functional exhaustion of T cells is not an irreversible state, and/or that resetting of anti-tumor immunity can result in an effective T cell response even at advanced cancer stages.

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